Review Article | Published:

Forkhead box transcription factors as context-dependent regulators of lymphocyte homeostasis


Lymphocytes have evolved to react rapidly and robustly to changes in their local environment by using transient adaptations and by regulating their terminal differentiation programmes. Forkhead box transcription factors (FTFs) can direct leukocyte-specific responses, and their functional diversification promotes a high degree of context-dependent specification. Many, often antagonistic, FTFs have overlapping expression patterns and can thereby compete for binding to the same chromosomal target sequences. Multiple molecular mechanisms also connect extracellular signals to the expression and functionality of specific FTFs and, in this way, fine-tune their activity. Through these diverse mechanisms, FTFs can function as context-dependent rheostats responding to diverse environmental stimuli. Focusing on the various mechanisms by which their functional activity is modulated, as well as on their mechanisms of action, we discuss how specific FTFs control lymphocyte function, allowing for the establishment and maintenance of immune homeostasis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Coffer, P. J. & Burgering, B. M. Forkhead-box transcription factors and their role in the immune system. Nat. Rev. Immunol. 4, 889–899 (2004).

  2. 2.

    Eijkelenboom, A. & Burgering, B. M. FOXOs: signalling integrators for homeostasis maintenance. Nat. Rev. Mol. Cell Biol. 14, 83–97 (2013).

  3. 3.

    Carlsson, P. & Mahlapuu, M. Forkhead transcription factors: key players in development and metabolism. Dev. Biol. 250, 1–23 (2002).

  4. 4.

    Benayoun, B. A., Caburet, S. & Veitia, R. A. Forkhead transcription factors: key players in health and disease. Trends Genet. 27, 224–232 (2011).

  5. 5.

    Hedrick, S. M. The cunning little vixen: Foxo and the cycle of life and death. Nat. Immunol. 10, 1057–1063 (2009).

  6. 6.

    Hedrick, S. M., Hess Michelini, R., Doedens, A. L., Goldrath, A. W. & Stone, E. L. FOXO transcription factors throughout T cell biology. Nat. Rev. Immunol. 12, 649–661 (2012).

  7. 7.

    Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

  8. 8.

    Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).

  9. 9.

    Wildin, R. S. et al. X-Linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).

  10. 10.

    Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

  11. 11.

    Lin, W. et al. Regulatory T cell development in the absence of functional Foxp3. Nat. Immunol. 8, 359–368 (2007).

  12. 12.

    Feuerer, M., Hill, J. A., Mathis, D. & Benoist, C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat. Immunol. 10, 689–695 (2009).

  13. 13.

    Khattri, R. et al. The amount of scurfin protein determines peripheral T cell number and responsiveness. J. Immunol. 167, 6312–6320 (2001).

  14. 14.

    Schubert, L. A., Jeffery, E., Zhang, Y., Ramsdell, F. & Ziegler, S. F. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem. 276, 37672–37679 (2001).

  15. 15.

    Liu, Y. et al. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nat. Med. 20, 272–282 (2014). This is a description of a novel, FOXA1-dependent type of T reg cell.

  16. 16.

    Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).

  17. 17.

    Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell 9, 279–289 (2002).

  18. 18.

    Lee, C. S., Friedman, J. R., Fulmer, J. T. & Kaestner, K. H. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005).

  19. 19.

    Hu, H. et al. Foxp1 is an essential transcriptional regulator of B cell development. Nat. Immunol. 7, 819–826 (2006). This describes a role for FOXP1 during B cell maturation.

  20. 20.

    van Keimpema, M. et al. FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-kappaB to promote survival of human B cells. Blood 124, 3431–3440 (2014).

  21. 21.

    Sagardoy, A. et al. Downregulation of FOXP1 is required during germinal center B cell function. Blood 121, 4311–4320 (2013).

  22. 22.

    van Keimpema, M. et al. The forkhead transcription factor FOXP1 represses human plasma cell differentiation. Blood 126, 2098–2109 (2015).

  23. 23.

    Feng, X. et al. Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development. Blood 115, 510–518 (2010).

  24. 24.

    Feng, X. et al. Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells. Nat. Immunol. 12, 544–550 (2011).

  25. 25.

    Wei, H. et al. Cutting edge: Foxp1 controls naive CD8+ T cell quiescence by simultaneously repressing key pathways in cellular metabolism and cell cycle progression. J. Immunol. 196, 3537–3541 (2016).

  26. 26.

    Durek, P. et al. Epigenomic profiling of human CD4(+) T cells supports a linear differentiation model and highlights molecular regulators of memory development. Immunity 45, 1148–1161 (2016).

  27. 27.

    Wang, H. et al. The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells. Nat. Immunol. 15, 667–675 (2014).

  28. 28.

    Ouyang, W., Beckett, O., Flavell, R. A. & Li, M. O. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 30, 358–371 (2009). This study describes a role for FOXO proteins in T reg cell function.

  29. 29.

    Kerdiles, Y. M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176–184 (2009). This is a description of a role for FOXO1 in naive T cell survival.

  30. 30.

    van der Horst, A. & Burgering, B. M. Stressing the role of FoxO proteins in lifespan and disease. Nat. Rev. Mol. Cell Biol. 8, 440–450 (2007).

  31. 31.

    Deng, Y. et al. Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function. Immunity 42, 457–470 (2015). This is a description of a role for FOXO1 in NK cell differentiation.

  32. 32.

    Stone, E. L. et al. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42, 239–251 (2015). This study describes a role for FOXO1 in T FH cell differentiation.

  33. 33.

    Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

  34. 34.

    Laine, A. et al. Foxo1 is a T cell-intrinsic inhibitor of the RORgammat-Th17 program. J. Immunol. 195, 1791–1803 (2015).

  35. 35.

    Ichiyama, K. et al. The microRNA-183-96-182 cluster promotes T Helper 17 cell pathogenicity by negatively regulating transcription factor Foxo1 expression. Immunity 44, 1284–1298 (2016).

  36. 36.

    Wohlfert, E. A., Gorelik, L., Mittler, R., Flavell, R. A. & Clark, R. B. Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J. Immunol. 176, 1316–1320 (2006).

  37. 37.

    Harada, Y. et al. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J. Exp. Med. 207, 1381–1391 (2010).

  38. 38.

    Ouyang, W. et al. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 491, 554–559 (2012). This study demonstrates that FOXO1 has an essential role in T reg cell function.

  39. 39.

    Ouyang, W. et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat. Immunol. 11, 618–627 (2010). This paper reveals that both FOXO1 and FOXO3 collaborate in the induction of T reg cells.

  40. 40.

    Fabre, S. et al. FOXO1 regulates L-Selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase. J. Immunol. 181, 2980–2989 (2008).

  41. 41.

    Debes, G. F. et al. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat. Immunol. 6, 889–894 (2005).

  42. 42.

    Bromley, S. K., Thomas, S. Y. & Luster, A. D. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat. Immunol. 6, 895–901 (2005).

  43. 43.

    Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

  44. 44.

    Luo, C. T., Liao, W., Dadi, S., Toure, A. & Li, M. O. Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity. Nature 529, 532–536 (2016). This paper shows that the TCR-mediated activation of T reg cells leads to FOXO1 degradation and, in this way, promotes the egress of cells from the lymph node.

  45. 45.

    Zhang, N. et al. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity 30, 458–469 (2009).

  46. 46.

    Lin, L. & Peng, S. L. Coordination of NF-kappaB and NFAT antagonism by the forkhead transcription factor Foxd1. J. Immunol. 176, 4793–4803 (2006).

  47. 47.

    Srivatsan, S. & Peng, S. L. Cutting edge: Foxj1 protects against autoimmunity and inhibits thymocyte egress. J. Immunol. 175, 7805–7809 (2005).

  48. 48.

    Lin, L., Spoor, M. S., Gerth, A. J., Brody, S. L. & Peng, S. L. Modulation of Th1 activation and inflammation by the NF-kappaB repressor Foxj1. Science 303, 1017–1020 (2004). This paper demonstrates a role for FOXJ1 in T cell homeostasis.

  49. 49.

    Lin, L., Brody, S. L. & Peng, S. L. Restraint of B cell activation by Foxj1-mediated antagonism of NF-kappa B and IL-6. J. Immunol. 175, 951–958 (2005).

  50. 50.

    Tan, J. T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98, 8732–8737 (2001).

  51. 51.

    Rao, R. R., Li, Q., Gubbels Bupp, M. R. & Shrikant, P. A. Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. Immunity 36, 374–387 (2012).

  52. 52.

    Huster, K. M. et al. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Proc. Natl Acad. Sci. USA 101, 5610–5615 (2004).

  53. 53.

    Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191–1198 (2003).

  54. 54.

    Tejera, M. M., Kim, E. H., Sullivan, J. A., Plisch, E. H. & Suresh, M. FoxO1 controls effector-to-memory transition and maintenance of functional CD8 T cell memory. J. Immunol. 191, 187–199 (2013).

  55. 55.

    Hess Michelini, R., Doedens, A. L., Goldrath, A. W. & Hedrick, S. M. Differentiation of CD8 memory T cells depends on Foxo1. J. Exp. Med. 210, 1189–1200 (2013).

  56. 56.

    Kim, M. V., Ouyang, W., Liao, W., Zhang, M. Q. & Li, M. O. The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection. Immunity 39, 286–297 (2013). References 51, 54, 55 and 56 describe a role for FOXO1 in memory T cell formation.

  57. 57.

    Delpoux, A., Lai, C. Y., Hedrick, S. M. & Doedens, A. L. FOXO1 opposition of CD8(+) T cell effector programming confers early memory properties and phenotypic diversity. Proc. Natl Acad. Sci. USA 114, E8865–E8874 (2017).

  58. 58.

    Zhang, L. et al. Mammalian target of rapamycin complex 2 controls CD8 T cell memory differentiation in a Foxo1-dependent manner. Cell Rep. 14, 1206–1217 (2016).

  59. 59.

    Utzschneider, D. T. et al. Active maintenance of T cell memory in acute and chronic viral infection depends on continuous expression of FOXO1. Cell Rep. 22, 3454–3467 (2018).

  60. 60.

    Delpoux, A. et al. Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8(+) T cells. J. Exp. Med. 215, 575–594 (2018).

  61. 61.

    Araki, K. et al. mTOR regulates memory CD8 T cell differentiation. Nature 460, 108–112 (2009).

  62. 62.

    Pearce, E. L. et al. Enhancing CD8 T cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

  63. 63.

    Sullivan, J. A., Kim, E. H., Plisch, E. H., Peng, S. L. & Suresh, M. FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms. PLOS Pathog. 8, e1002533 (2012).

  64. 64.

    Tzelepis, F. et al. Intrinsic role of FoxO3a in the development of CD8+ T cell memory. J. Immunol. 190, 1066–1075 (2013).

  65. 65.

    Amin, R. H. & Schlissel, M. S. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nat. Immunol. 9, 613–622 (2008).

  66. 66.

    Herzog, S. et al. SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway. Nat. Immunol. 9, 623–631 (2008). References 65 and 66 demonstrate a role for FOXO1 in B cell maturation.

  67. 67.

    De Silva, N. S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Rev. Immunol. 15, 137–148 (2015).

  68. 68.

    Sander, S. et al. PI3 kinase and FOXO1 transcription factor activity differentially control B cells in the germinal center light and dark zones. Immunity 43, 1075–1086 (2015).

  69. 69.

    Dominguez-Sola, D. et al. The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity 43, 1064–1074 (2015).

  70. 70.

    Inoue, T. et al. The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help. J. Exp. Med. 214, 1181–1198 (2017). References 68–70 reveal that FOXO1 is involved in the regulation of B cell GC reactions.

  71. 71.

    Eijkelenboom, A. et al. Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling. Mol. Syst. Biol. 9, 638 (2013).

  72. 72.

    Eijkelenboom, A., Mokry, M., Smits, L. M., Nieuwenhuis, E. E. & Burgering, B. M. FOXO3 selectively amplifies enhancer activity to establish target gene regulation. Cell Rep. 5, 1664–1678 (2013).

  73. 73.

    Samstein, R. M. et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151, 153–166 (2012). This study demonstrates complex interactions between FTFs that govern T reg cell development.

  74. 74.

    Rudra, D. et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat. Immunol. 13, 1010–1019 (2012).

  75. 75.

    van Boxtel, R. et al. FOXP1 acts through a negative feedback loop to suppress FOXO-induced apoptosis. Cell Death Differ. 20, 1219–1229 (2013).

  76. 76.

    Kerdiles, Y. M. et al. Foxo transcription factors control regulatory T cell development and function. Immunity 33, 890–904 (2010). This study characterizes the role of FOXO proteins in T reg cell function.

  77. 77.

    Ouyang, W. & Li, M. O. Foxo: in command of T lymphocyte homeostasis and tolerance. Trends Immunol. 32, 26–33 (2011).

  78. 78.

    Essers, M. A. et al. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308, 1181–1184 (2005).

  79. 79.

    Hoogeboom, D. et al. Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity. J. Biol. Chem. 283, 9224–9230 (2008).

  80. 80.

    van Loosdregt, J. et al. Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity 39, 298–310 (2013).

  81. 81.

    Walker, M. P. et al. FOXP1 potentiates Wnt/beta-catenin signaling in diffuse large B cell lymphoma. Sci. Signal 8, ra12 (2015).

  82. 82.

    Wehrens, E. J. et al. Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. Blood 118, 3538–3548 (2011).

  83. 83.

    Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).

  84. 84.

    Lozano, T. et al. Inhibition of FOXP3/NFAT interaction enhances T cell function after TCR stimulation. J. Immunol. 195, 3180–3189 (2015).

  85. 85.

    Thompson, M. G. et al. FOXO3-NF-kappaB RelA protein complexes reduce proinflammatory cell signaling and function. J. Immunol. 195, 5637–5647 (2015).

  86. 86.

    Bettelli, E., Dastrange, M. & Oukka, M. Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc. Natl Acad. Sci. USA 102, 5138–5143 (2005).

  87. 87.

    Gerondakis, S., Fulford, T. S., Messina, N. L. & Grumont, R. J. NF-kappaB control of T cell development. Nat. Immunol. 15, 15–25 (2014).

  88. 88.

    Long, M., Park, S. G., Strickland, I., Hayden, M. S. & Ghosh, S. Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921–931 (2009).

  89. 89.

    Li, Q. & Verma, I. M. NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).

  90. 90.

    Tone, Y. et al. Gene expression in the Gitr locus is regulated by NF-kappaB and Foxp3 through an enhancer. J. Immunol. 192, 3915–3924 (2014).

  91. 91.

    Zhang, F., Meng, G. & Strober, W. Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat. Immunol. 9, 1297–1306 (2008).

  92. 92.

    Zhou, L. et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453, 236–240 (2008).

  93. 93.

    Chen, Z. et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39, 272–285 (2013).

  94. 94.

    van Loosdregt, J. et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39, 259–271 (2013). References 80, 93 and 94 show that external signals control T reg cell function by influencing the stability of FOXP3.

  95. 95.

    van Loosdregt, J. & Coffer, P. J. Post-translational modification networks regulating FOXP3 function. Trends Immunol. 35, 368–378 (2014).

  96. 96.

    Zhao, Y. et al. E3 ubiquitin ligase Cbl-b regulates thymic-derived CD4+CD25+ regulatory T cell development by targeting Foxp3 for ubiquitination. J. Immunol. 194, 1639–1645 (2015).

  97. 97.

    Yang, J. Y. et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat. Cell Biol. 10, 138–148 (2008).

  98. 98.

    Hu, M. C. et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225–237 (2004).

  99. 99.

    Plas, D. R. & Thompson, C. B. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J. Biol. Chem. 278, 12361–12366 (2003).

  100. 100.

    Huang, H. et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc. Natl Acad. Sci. USA 102, 1649–1654 (2005).

  101. 101.

    Wang, D. et al. Inhibition of S-phase kinase-associated protein 2 (Skp2) reprograms and converts diabetogenic T cells to Foxp3 +regulatory T cells. Proc. Natl Acad. Sci. USA 109, 9493–9498 (2012).

  102. 102.

    Grabbe, C., Husnjak, K. & Dikic, I. The spatial and temporal organization of ubiquitin networks. Nat. Rev. Mol. Cell Biol. 12, 295–307 (2011).

  103. 103.

    van der Horst, A. et al. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat. Cell Biol. 8, 1064–1073 (2006).

  104. 104.

    Chunder, N., Wang, L., Chen, C., Hancock, W. W. & Wells, A. D. Cyclin-dependent kinase 2 controls peripheral immune tolerance. J. Immunol. 189, 5659–5666 (2012).

  105. 105.

    Morawski, P. A., Mehra, P., Chen, C., Bhatti, T. & Wells, A. D. Foxp3 protein stability is regulated by cyclin-dependent kinase 2. J. Biol. Chem. 288, 24494–24502 (2013).

  106. 106.

    Nie, H. et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat. Med. 19, 322–328 (2013).

  107. 107.

    Fox, C. J., Hammerman, P. S. & Thompson, C. B. The Pim kinases control rapamycin-resistant T cell survival and activation. J. Exp. Med. 201, 259–266 (2005).

  108. 108.

    Basu, S., Golovina, T., Mikheeva, T., June, C. H. & Riley, J. L. Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J. Immunol. 180, 5794–5798 (2008).

  109. 109.

    Deng, G. et al. Pim-2 kinase influences regulatory T cell function and stability by mediating Foxp3 protein N-terminal phosphorylation. J. Biol. Chem. 290, 20211–20220 (2015).

  110. 110.

    Du, X. et al. Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease. J. Immunol. 192, 1525–1535 (2014).

  111. 111.

    Tomiyama, T. et al. Antigen-specific suppression and immunological synapse formation by regulatory T cells require the Mst1 kinase. PLOS One 8, e73874 (2013).

  112. 112.

    Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

  113. 113.

    Choi, J. et al. Mst1-FoxO signaling protects naive T lymphocytes from cellular oxidative stress in mice. PLOS One 4, e8011 (2009).

  114. 114.

    van Loosdregt, J. et al. Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115, 965–974 (2010).

  115. 115.

    Li, B. et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl Acad. Sci. USA 104, 4571–4576 (2007).

  116. 116.

    Liu, Y. et al. Inhibition of p300 impairs Foxp3(+) T regulatory cell function and promotes antitumor immunity. Nat. Med. 19, 1173–1177 (2013). This paper demonstrates the potential for modulating FOXP3 acetylation therapeutically.

  117. 117.

    van Loosdregt, J. et al. Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PLOS One 6, e19047 (2011).

  118. 118.

    Tao, R. et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat. Med. 13, 1299–1307 (2007).

  119. 119.

    Kwon, H. S. et al. Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J. Immunol. 188, 2712–2721 (2012).

  120. 120.

    Beier, U. H. et al. Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol. Cell. Biol. 31, 1022–1029 (2011).

  121. 121.

    Akimova, T. et al. Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs. Clin. Immunol. 136, 348–363 (2010).

  122. 122.

    Jeng, M. Y. et al. Metabolic reprogramming of human CD8(+) memory T cells through loss of SIRT1. J. Exp. Med. 215, 51–62 (2018).

  123. 123.

    Fagnoni, F. F. et al. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology 88, 501–507 (1996).

  124. 124.

    Song, X. et al. Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function. Cell Rep. 1, 665–675 (2012).

  125. 125.

    Yamagata, K. et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol. Cell 32, 221–231 (2008).

  126. 126.

    Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).

  127. 127.

    Wang, F. et al. Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation. Oncogene 31, 1546–1557 (2012).

  128. 128.

    van Gent, R. et al. SIRT1 mediates FOXA2 breakdown by deacetylation in a nutrient-dependent manner. PLOS One 9, e98438 (2014).

Download references


We would like to apologise to any authors whose work could not be cited due to space contstraints. The Zaiss laboratory is supported by the Medical Research Council, grant MR/M011755/1, and the European Union, grant CIG-631413 (“EGF-R for Immunity”). The Coffer laboratory is supported by grants from the Dutch Cancer Society (UU 2015-7838) and Dutch Reumatology Foundation (16-1-301)

Reviewer information

Nature Reviews Immunology thanks M. Suresh and the other anonymous reviewer(s) for their help with the peer review of this manuscript.

Author information

Both authors contributed to the researching of data, discussion of content and writing, reviewing and editing of the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Dietmar M. W. Zaiss or Paul J. Coffer.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1: Role of FTFs during B cell maturation and functioning.
Fig. 2: Role of FTFs during T cell maturation and functioning.
Fig. 3: FOXO-mediated regulation of T cell homing.
Fig. 4: Control of memory CD8+ T cell generation by FOXO1.
Fig. 5: Interactions between FTFs and cofactors in lymphocytes.
Fig. 6: Post-translational modifications control FTF transcriptional output.